3-Oximino-17{60 -propadienyl-substituted-4-gonenes

ABSTRACT

The compounds are 3-oximino-17 Alpha -propadienyl-substituted steroids, e.g. 17 Alpha -propadienylestra-4-en-17 Beta -ol-3-one oxime and are useful in the regulation of reproduction in warmblooded animals.

United States Patent Basco et al.

[451 Sept. 23, 1975 3-OXIMINO-l7a-PROPADIENYL-SUB- STITUTED-4-GONENES Inventors: Imre Basco, Morristown, N.J.;

Eugene E. Galantay, Liestal, Switzerland Assignee: Sandoz Inc., East Hanover, NJ.

Filed: Sept. 19, 1973 Appl. No.: 398,584

Related U.S. Application Data Continuation-impart of Ser. No. 154,190, June 17, 1971.

U.S. Cl. 260/397.5; 424/238; 260/397.45 Int. Cl. C07,] 43/00 References Cited UNITED STATES PATENTS 10/1965 Mazur 260/397.1

3,299,107 1/1967 Mazur 260/3975 3,501,508 3/1970 3,507,888 4/1970 Klimstra 260/3973 3,532,689 10/1970 Shroff 260/239.55

Primary Examiner-Elbert L. Roberts Attarne y, Agent, or Firm-Gera1d D. Sharkin; Richard E. Vila; Frederick H. Weinfeldt 6 Claims, No Drawings 3-OXIMINO- l 7a-PROPADIENYL-SUBSTITUTED-4- GONENES This is a continuation-in-part of copending application Ser. No. 154.190 (filed June 17. 1971).

This invention relates to steroidal compounds. and more particularly to 3-oximino-l7a-propadienyl-substituted-4-gonenes. and to the preparation of such compounds as well as to therapeutic compositions which contain such compounds and the use of such compounds.

The compounds of this invention. i.e.. Compounds l. are conveniently represented by the formula:

wherein R is a hydrogen atom or lower alkanoyl. c.g. having from two to four carbon atoms. such as acetyl. propionyl and butyryl. including isomeric forms where they exist. but are preferably unbranched: R is unbranched alkyl having from one to three carbon atoms. i.e.. methyl. ethyl or n-propyl; and each R and R is. independently. a hydrogen atom or methyl; provided that R and R are not both methyl.

Compounds I include three classes of compounds. i.e. Compounds la. lb and It' wherein R and R are as defined above:

RON

Compounds l are prepared from suitable 3-ketones. i.e.. Compounds ll;

wherein R. R and R and the proviso pertaining thereto are as defined above. by conventional means for preparing an oxime derivative from a 3-ketosteroid (Process a). For example, by treatment of a suitable 3- keto steroid (11) with a suitable hydroxylamine reagent. to yield the oxime. i.e.. a Compound I wherein R is a hydrogen atom. and further treatment thereof where a Compound I is desired wherein R is alkanoyl. with an alkanoylating agent (Process b).

There are accordingly three classes of Compound 11. i.e.. Ila. III; and [la corresponding to Compoundsla. lb and lo. respectively. which are described above.

3-Keto steroids suitable as starting materials for the preparation of Compounds l are described in the literature. c.g. in Belgian Pat. Nos. 742.137; 766.147; 767.430 and 767.43]. and US. Pat. Nos. 3.661.940 and 3.723.483.

A suitable starting material for a Compound lh may be obtained in the manner described in the US. Pat. No. 3.377.366 (issued Apr. 9. 1968) and those com pounds not known may be prepared in a manner analogous to that for preparing the known compounds. Said starting material is a 3-methoxy-l lB-methylgona- 2.5( l0)-dien-l7-one which by treatment analogous to the series of reaction steps described in the abovementioned patents yields an 1 1B-methyl-l7apropadienylgona-4-en-l7,B-ol-3-one. suitable for use as a Compound Ill).

Compounds of Class 10 may be prepared by employing a 3-lower alkoxy-9a-methylgona-l.3.5( l0)-trien- 17one. e.g. 9a-methylestr0ne methylether. which is described. e.g.. in Belgian Pat. No. 753.779. by a series of steps involving subjecting such l7-keto-triene to Birch reduction conditions to obtain the corresponding 2.5( l0)-dien-l7B-ol which is then treated so as to oxidize the l7-hydroxy function to an oxo function therebyobtaining a l7-keto compound which is then subjected to treatment analogous to the series of process steps described in the above-mentioned Belgian Patents to obtain the 9rx-methyl l7a-propadienylgona- 4-en-l7B-ol-3-one (a Compound llc). which may then be reacted to form the 3-oxime derivative thereof (i.e.. a Compound lc).

A convenient method for carrying out Process (a) to obtain a Compound I wherein R is a hydrogen atom. involves treating 21 Compound ll. under anhydrous conditions. with a hydroxylamine reagent preferably hydroxylamine acetate in an inert organic solvent. eg a lower alkanol. such as methanol or ethanol. at moderate temperatures. e.g..convcniently at room temperature. or at other temperatures preferably lower than the reflux temperature of the solvent. The hydroxylamine reagent may be prepared separately or in situ. e.g. from a hydroxylamine salt. c.g. the hydrochloride. and a base such as sodium acetate, sodium hydroxide or pyridine. Where pyridine is employed as base. it may serve in excess as solvent for the reaction.

A convenient method of carrying out Process (b)'to obtain a Compound I wherein R is lower alkanoyl. involves treating a Compound I wherein R is a hydrogen atom. with an alkanoylating agent. It is preferred that in Process (h) alkanoylating agents which are not strongly acidic be employed, the l'la-propadienyL substituent may be adversely affected by such conditions. A lower aliphatic acid or acid anhydride may be used as the alkanoylating agent in the presence of an acid binding agent. c.g. acetic acid anhydride with pyridine. The alkanoylation reaction may becarried in an inert organic solvent. e.g. benzene, at moderate temperatures. e.g. l to 50C.. preferably at rooni temperature. Where the alkanoylating agent is suitable as a solvent. it may be used in excess to serve as solvent.

The Compounds I prepared as described above may be recovered and refined by means conventional in the art. cg. by recrystallization or column or layer chromatography.

The compounds of formula (I) are useful because they possess pharmacological properties in animls. In particular, such compounds exhibit a combination of progestational and estrogenic activity and are therefore useful in the control offcrtility in female warm-blooded animals and regulations of estrus or the menstrual function thereof, and in addition are also useful as luteolytic agents in the prevention or interruption of pregnancy in such animals. The progestational activity is indicated by the well-known Clauberg test; the method basically described in Endrocrinology63 (1958) 464 wherein a rabbit is given 0.00] to 1.0 milligrams of active agent. The estrogenic activity is indicated by observing increase in white mouse uterine weight. e.g. as described in Endocrinology 65. 265 (1959) or by observing for cornification of vaginal epithelium of adult female ovariecomized white rats scored according to the method of Biggers and Claringbold. when said animals are given from 0.001 to milligrams of active agent. Luteolytic activity is indicated by selecting female estrous whiterats from a colony. treating them for 4 days and then caging them with fertile males; beginning on the following day, the females are treated for an additional 10 days with the compound being tested; and on the third day following the last treatment the females are sacrificed and the uteri checked for implantation sites (the absence or regression of which being taken as a positive result). Luteolytic activity may also he indicated by a rabbit pseudopregnaney test in whichadult Ne Zealand White female rabbits are injected intravenously with 100 international units of Huinan' Chorionic (ionadotrophin (HCG) to induce ovulation and formation of corpora lutea (pseudopregnancy). The day oftreatment with HCG is considered day-l of pseudopregnancy. lmmediatelyprior to the HCG treatment a 2 ml. blood sample (via heart puncture) is collected. Two ml. blood samples are obtained on various days thereafter through day-l2 of pseudopregnancy. On day-3 of pseudopregnancy groups of females are treated orally or injected subcutaneously with corn oil (controls) or various compounds in corn oil. Treatments are continued through day8 of pseudopregnancy. Blood samples are analyzed for progestin eontent accordin gto the method of .lohansson et al. (Endocrinology Vol. 82; l43l48. 1968). A compound is judged to be luteolytic if plasma progestin levels have returned to pretreatment levels by day-l2 of pseudopregnancy.

These compounds may be combined with a pharmaceutically acceptable carrier or adjuvant in a manner which is conventional in the pharmaceutical art. They may be administered orally 'or parenterally. The dosage will vary depending upon the mode of administration utilized and the particular compound employed. However. in general. satisfactory results are obtained in female warm-blooded animals. e.g. mammals. when the compounds are administered at a daily dosage of from about 0.005 mg. to'30 mg.. e.g. about 0.015 mg. to l0 mg. to control fertility or regulate estrus or the menstrual function; and for the prevention or interruption of pregnancy by luteolytic activity ata daily dosage of from about l mg. to mg.. c.g. from about l mg. to 20 mg, daily for from about I to 6 days during the luteal phase. Convenient dosage forms suitable for internal administration comprise from about 0.005 mg. to 100 mg, e.g. from 'about 0.015 to 20 mg. of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

A representative formulation suitable for oral administration is a capsuletZSO mg.) prepared by standard techniques which contains the following:

Ingredient Weight tmg.)

l7a-propadienylestra-4-en l 7B-ol-3 one oxime 5 245 ln the following examples illustrating the invention, all temperatures are C. and room temperature is 20 to 30C.. unless indicated otherwise.

EXAMPLE l l7a-Propadienylestra-4-en-l 7B-ol-3-one oxime A solution of 5.0 g. of l7a-propadienylestfa-4-enl7B-ol-3-one in 42 ml. of absolute ethanol is mixed with a solution of hydroxylamine acetate (prepared from 3.32 g. of hydroxylamine hydrochloride and l 1.3 g. of sodium acetate trihydrate in 42 ml. of absolute ethanol, the resulting solids being filtered off). The resulting mixture is kept at room temperature for onehalf hour. The reaction mixture is then diluted with water and the solids which have separated are collected by filtration to give the title product. i701- propadienylestra-4-en'l7B-ol-3-one oxime. m.p. l0l to 164C.

EXAMPLE 2 l3-Ethyll 7a-propadienylgona-4-enl 7B-ol-3-one oxime Repeating the procedure described in Example 1 but replacing the l7a-propadienylestra-4 enl 7Bol-3-one used therein with an equivalent amount of 13-ethyl- 17a-propadienylgonal-en-l7B-ol 3 one there is obtained l 3-ethyl-17oz-propadienylgona-4-en-l7Bol- 3-one oxime. V

EXAMPLE 3 l IB-Methyl-l7a-propadienylestra-4'en-17B-o1-3-one oxime Step A: 3-Methoxy11,B-methyl-l7a-N.N dimethylaminopropynlestra-Z.5( )-dien-l 73-01 A total of 1.8 g of lithium is added in small portions to 120 ml of ethylenediamine with stirring at a temperature of 50 60 under nitrogen. After addition is complete. the blue solution is heated at 75 85for 1 /2 hours whereat a pale yellow reaction mixture is obtained. This mixture is then cooled to 10, and 20 g of N.N-dimethylamino-2-propyne is added dropwise over 5 minute. Stirring is continued at room temperature for 1 hour. at which point a solution of 2.6 g of 3-methoxyl l,8-methylestra-2.5( 10)-dien-17-one in 40 ml oftetrahydrofuran is added. The mixture is now stirred at room temperature for 4 hours; and after cooling in an ice-water mixture. 100 ml of brine are added under nitrogen followed by 250 ml of ether. The two layers are separated. and the aqueous layer is extracted three times with benzene. The combined organic phases are washed with brine and dried over sodium sulfate. After removal of the solvents. the residue is crystallized from ether to yield 3-methoxy-1 1B-methyl-17a-N.N- dimethylaminopropynylestra-2.5( 10 )-dien- 1 713-01 (m.p. 170- 175). Step B: 3-Methoxy-1 1B-methyl-17a-NN- dimethylaminopropynylestra-2.5( lO)-dien-17B-ol methiodide To a solution of 2.5 g of 3-methoxy-l lB-methyl-17a- N.N-dimethylaminopropynylestra-2,5( 10)-dienl 713-01 in 60 ml of acetone is added ml of methyl iodide. The solution is kept at a temperature of 5 for 18 hours during which time a crystalline precipitate forms. This is filtered off and recrystallized from acetone to yield 3-methoxy-l 1B-methyl-17a-N.N- dimethylaminopropynlestra-Z,5( 10)-dien-1 73-01 thiodide. m.p. 255 260 (decomposition). Step C: 3-Methoxy-1IB-methyl-l7a-propadienylestra- 2.5( l0)-dien-l7B-ol To a suspension of 3.1 g of the iodide salt from Step B in 100 ml of anhydrous tetrahydrofuran. under ice cooling, is added 3 ml of a 70% solution of sodium di( methoxyethoxy) aluminum hydride lNaAlH- (OCH .CH .OCH;,) in benzene. diluted with 10 ml of tetrahydrofuran. The reaction mixture is allowed to warm to room temperature and stirred for a total of 2 hours at which time solution is complete. Water is then added to decompose the excess hydride and the tetrahydrofuran is removedunder reduced pressure. The aqueous residue is extracted with methylene chloride and the organic phase is dried over sodium sulfate. After removal of the solvent. the residue is crystallized from ether/hexane 1:2) to yield 3methoxy-l 1B- methyl- 1 7tx-propadienylestra2.5( l0 )-dien-1 75-01. m.p. 135.

Step 1): 1 lB-Methyl-l7u-propadienylestra-4-cn17B- ol-3-one To a solution of 800 mg of 3-methoxy-l Iii-methyl- 17oz-propadienylestra-Z.5( l0)-dienl7/3-ol in 10 ml of methanol is added 5 drops of concentrated hydrochloric acid and the mixture is left at room temperature for 1 /2 hours. The mixture is then diluted with ice/water and a saturated aqueous solution of sodium bicarbonate is cautiously added until the mixture is no longer acidic. The solution is then extracted with ether. and the organic phase after separation is dried over sodium sulfate. Evaporation of the solvent yields a residue which is crystallized from ether/hexane. 1:2) to give 1 lfi-methyl-l7a-propadienylestra-4-en-17,8-o1-3-one. m.p. l37 139C. Step E: 1 IB-Methyl-l 7a-propadienylestra-4en-17B- o1-3-one oxime Repeating the procedure of Example 1. but replacing the 17a-propadienylestra-4-en17/3-o1 3-one used therein with an equivalent amount of 1 1,8-methyl-17a propadienylestra-4-enl7B-3-one. there is obtained 1 1 B-methyl-l 7a-propadienylestra-4-en 17B-ol-3-one oxnne.

EXAMPLE 4 N-Acetoxy-17a-propadienylestra-4-en17B-ol-3-one oxime A solution of 3.0 g. of 17oz-propadienylestra-4enl7B-ol-3-one oxime (obtained in Example 1 in 30.0 ml of pyridine is treated with 10.0 ml of acetic anhydride and kept at room temperature for 1 hr. The solution is then diluted with ice water and the separated solids are collected by filtration to give N-acetoxy l7apropadieny1estra-4-en- 1 7B-o1-3-one oxime.

Repeating the procedure of this example. but using an equivalent amount of 1 lB'methyl-17apropadienylestra-4-en-17,8-ol 3-one oxime (Example 3) in place of the 17a-propadienylestra-4-en-17B-ol- 3-one oxime. there is similarly obtained N-acetoxyl lB-methyl- 1 7a-propadienylestra-4-enl 7,8-o1-3-one oxime.

EXAMPLE 5 )a-Methyl-l7a-propadienylestra-4-en-17/3-ol-3-one oxime Step A: 9a-Methy1-estra2.5(10)-dien-3.17Bdiol 3- methyl ether A solution of 6.0 g. of 9a-methylestrone methyl ether in ml of tetrahydrofuran and 90 ml of l-butanol is added to 200 m1 of ammonia under reflux. A total of 2.8 g. of lithium is then added in portions over 10 min and the resulting blue solution is stirred under reflux for 6 hrs. The ammonia is allowed to evaporate overnight and 50 ml of methanol is added to the residue followed by 300 ml of saturated aqueous sodium chloride and 200 ml of benzene. The two phases are separated and the organic layer is washed with saturated aqueous sodium chloride and 200 ml of benzene. The two phases are separated and the organic layer is washed with saturated aqueous sodium chloride. dried over anhy drous sodium sulphate and evaporated to give a residue which is crystallized from methanol. Thus is obtained )u-mcthylestra-Zj(l)-dien-3.l7-diol 3-methyl ether m.p. 116 120. 5

Step B: 3-Methoxy-9a-methylestra-2.5( l())-dienl7-one A mixture of 5.0 g of 9a-methylestra-2.5( l0)-dien-' methylestra-2,5( l0 )-dien-3, l 7B-diol 3-methyl ether A total of 2.2 g. of lithium is added portionwise to 150 ml. of ethylenediamine, stirred and maintained at a temperature of 5060 under nitrogen. After the addition is complete the blue solution is heated to 7585 for 1 /2 hrs. when a pale yellow reaction mixture is obtained. This is then cooled to 10 and 24 g of N,N- dimethylamino-2-propyne is added over 5 min. Stirring is continued at room temperature for 1 hr., when a solution of 3.2g. of 3-methoxy-9a-methylestra-2.5( l0)- dienl 7-one in 40 ml of tetrahydrofuran is added. The mixture is now stirred at room temperature for 16 hrs. After cooling (ice/water) 200 ml. of saturated sodium chloride are added under nitrogen, followed by 300 ml of benzene. The two layers are separated. the aqueous layer'cxtracted three times with benzene and the combined organic phases are washed with saturated sodium chloride before being dried over anhydrous sodium sulphate. After removal of the solvent there is obtained l7a-N.N-Dimethylanino-propynyl-9a-methylestra- 2,5( l0)-dien-3, l7B-diol 3-methyl ether as an oil which is used in the subsequent step. I Step D: The Quaternary Ammonium Salt To a solution of 3.8 g. of l7l1-N.N dimethylaminopropynyl-9a-methyl estra-2,5( l())-dien- 3. l 7B-diol 3-methyl ether in 90 ml of acetone is added 30 ml of methyl iodide. The solution is kept at a temperature of 5 for 18 hrs. during which time a crystalline precipitate forms. This is filtered off and recrystallized from methanol/acetone, l/S. to yield the quaternary salt product m.p. 240-243 (dec.). Step E: )a-Methyll 7a-propadienylestra-2.5( l0)-dien- 3. l7B-diol 3-methyl ether To a suspension of 3.3 g. of the above iodide salt in I00 ml of anhydrous tetrahydrofuran. under ice cooling is added 10 ml of a 70% solution of sodium di(methoxyethoxy) aluminum hydride in benzene diluted with ml of tetrahydrofuran. The reaction mixture is allowed to warm to room temperature and stirred for a total of 2 hrs. by which time solution is complete. Water is then added to decompose the excess hydride and the tetrahydrofuran is removed under reduced propadienylestra-2.5( l0 )-dien-3,l 7B-diol pressure. The aqueous residue is extracted with methylene chloride and the organic phase is dried over anhydrous sodium sulphate. .After removal of the solvent there is obtained the product. )d-methyl-l 7apropadienylestra-2,5 lO)-dien-3,l7B-diol 3 methyl ether as an oil sufficiently pure for use in the next step. Step F: 9a-Methyl-l7a-propadienylestra-4-en-l7B-ol 3-one To a solution of 600 mg of 9a-methyl-l7a- 3-methyl ether in 10 ml of methanol is added 5 drops of cone. hydrochloric acid and the mixture is left at room temperature for 1 /2 hrs. It is then diluted with ice/water and a saturated aqueous solution of sodium bicarbonate is slowly added until the mixture is no longer acidic. It is then extracted with ether and the organic solution is dried over anhydrous sodium sulphate. Removal of the solvent gives a residue which is crystallized from ether "to yield )a-methyl-l7a-propadienylestra-4-en-17B-ol EXAMPLE 6 Tablets and Capsules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in the control of fertility in mammals:

Weight (mg) Ingredient Tahlet Capsule l7oz-Propadienylestra'men- 0.5 0.5 l7B-ol-3-onc oximc tragacanth l0 lactose 247 299.5

corn starch 25 talcum l5 magnesium stearate 2.5

Total mg 300 mg EXAMPLES 7 and 8 I Sterile Suspension for Injection and Oral Liquid Suspension The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional tachniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the control of fertility in mammals. The injectable suspension and oral liquid suspension are suitably administered once a day for this purpose.

-continucd Weight (mg) Stcrilc Oral lngrcdicnts lnjcctahlc Su- Liquid Su- SPCnStOn spensinn Polyvinylpyrrolidonc 5 Lecithin 3 Bcnzyl alcohol 0.01 Magnesium aluminum silicate 47.5 Flavor q.s Color q.s. Methyl purahcn. U.S.P. 4.5 Propyl parahcn. U.S.P. l.() Polysorbatc 80 (c.g. Tween 80) U.S.Pi S Sorhitol solution. 707:, U.S.P. 2.500 Buft'cr agent to adjust pH for desired qs q.s. stability Water for injection. qs to qs quantity sufficicnt.

What is claimed is:

l. A compound of the formula:

RON

whc rcin R is a hydrogen atom or alkanoyl having from two to four carbon atoms: and 

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 which is 17 Alpha -propadienylestra-4-en-17 Beta -ol-one oxime.
 3. The compound of claim 1 which is N-acetoxy-17 Alpha -propadienyl-estra-4-en-17 Beta -ol-3-one oxime.
 4. A compound of claim 1 in which R1 is methyl.
 5. A compound of claim 1 in which R is a hydrogen atom.
 6. A compound of claim 1 in which R is alkanoyl having from two to four carbon atoms. 